BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer

• DOI: 10.1007/s10549-011-1443-0
• Publication Date: 2011-03-25T15:39:44Z
• Authors: Michelle W. Wong; Cecilia Nordfors; David Mossman; Gordana Pecenpete...; Kelly A. Avery-Ki...; Bente Talseth-Palmer; Nikola A. Bowden; Rodney J. Scott
• Keywords: Adult; Male; DNA Mutational Analysis; BRIP1; Breast Neoplasms; Polymorphism, Single Nucleotide; 03 medical and health sciences; 0302 clinical medicine; 616; Humans; Genetic Predisposition to Disease; Ovarian Neoplasms; RAD51C; Base Sequence; Tumor Suppressor Proteins; Australia; Nuclear Proteins; hereditary breast cancer; Sequence Analysis, DNA; Middle Aged; Fanconi Anemia Complementation Group Proteins; 3. Good health; DNA-Binding Proteins; PALB2; Mutation; germline mutations; Female; Fanconi Anemia Complementation Group N Protein; RNA Helicases

Mutations in the recognized breast cancer susceptibility genes BRCA1, BRCA2, TP53, ATM, and CHEK2 account for approximately 20% of hereditary breast cancer. This raises the possibility that mutations in other biologically relevant genes may be involved in genetic predisposition to breast cancer. In this study, BRIP1, PALB2, and RAD51C were sequenced for mutations as a result of previously being associated with breast cancer risk due to their role in the double-strand break repair pathway and their close association with BRCA1 and BRCA2. Two truncating mutations in PALB2 (Q66X and W1038X), one of which is has not been reported before, were detected in an independent Australian cohort of 70 individuals with breast or ovarian cancer, and have strong family histories of breast or breast/ovarian cancer. In addition, six missense variants predicted to be causative were detected, one in BRIP1 and five in PALB2. No causative variants were identified in RAD51C. This study supports recent observations that although rare, PALB2 mutations are present in a small but substantial proportion of inherited breast cancer cases, and indicates that RAD51C at a population level does not account for a substantial number of familial breast cancer cases.